Clinical pathological correlations for human genetic disorders affecting the nervous system are important for the successful development of diagnostic techniques and therapeutic strategies. This goal is also facilitated by a comprehensive knowledge of the biochemistry and clinical heterogeneity of these disorders. Gaucher disease, the most common sphingolipidosis, is extremely useful as a model because of the occurrence of both neuronopathic and non-neuronopathic phenotypes. The basis of the broad spectrum of clinical diversity within the major types of the disorder can also be studied. Once the pathophysiologic mechanisms of systemic involvement in this enzyme deficiency disorder are understood and treatable, the therapy of nervous system dysfunction may be more rationally approached. Basic research on glucocerebrosidase, the enzyme deficient in Gaucher disease, has generated a more detailed understanding of the structure, biosynthesis, intracellular, routing,_ and turnover of the enzyme. These studies complement other studies within our branch focusing on the investigation of the potential and efficacy of gene transfer as a therapeutic approach. Targeted homologous recombination in embryonic stem cells is used to develop appropriate transgenic animal models of Gaucher disease and other genetic disorders. Recombinant active enzymes are being produced in the milk of transgenic animals. Recombinant production of human enzymes and activator proteins is directed toward the development of effective replacement and gene transfer therapy.